Summary of Septerna's Conference Call Company Overview - **Company**: Septerna - **Industry**: Biopharmaceuticals, specifically focused on GPCR (G protein-coupled receptor) drug discovery Key Points and Arguments Pipeline and Drug Development - Septerna is advancing its pipeline, particularly with the MRGPRX2 program, which has shown promising phase 1 data indicating differentiation from existing drugs and effective pharmaceutical properties, including the complete abrogation of the inflammatory cascade [1][4] - The company is also developing an oral PTH (parathyroid hormone) agonist, SEP-479, aimed at treating hyperparathyroidism, which is expected to enter clinical trials soon [1][21] MRGPRX2 Program - The MRGPRX2 program is focused on a negative allosteric modulator, SEP-631, which has demonstrated a potent effect in preclinical models, showing complete knockdown of skin extravasation in response to agonists [5][10] - Phase 1 trial results indicate that SEP-631 was well-tolerated with no serious adverse events, a half-life of approximately 24 hours, and no food effect, suggesting potential for once-daily oral dosing [13][18] - The upcoming phase 2 trial for chronic spontaneous urticaria is planned for the second half of the year, with a focus on dose-ranging and placebo-controlled design [20][31] SEP-479 Program - SEP-479 is a selective small molecule agonist for the PTH1 receptor, aimed at patients who have lost their parathyroid glands, leading to low calcium levels [21][22] - Preclinical studies have shown that SEP-479 can normalize serum calcium levels and has a long projected human half-life of 40-80 hours, with IND-enabling studies nearing completion [23][27] - The phase 1 trial for SEP-479 is set to begin in Australia, with a focus on safety and efficacy in healthy volunteers [28][44] Market Opportunity - Both programs target significant unmet medical needs, with MRGPRX2 involved in various conditions such as chronic spontaneous urticaria, asthma, and atopic dermatitis, while SEP-479 addresses hyperparathyroidism [19][21] - The company is well-capitalized, with a cash runway extending into at least 2029, allowing for continued investment in its pipeline [4] Additional Insights - The Native Complex Platform developed by Septerna is designed to unlock difficult GPCR targets, which has led to a robust portfolio of drug candidates [3][4] - The company is exploring multiple indications for its MRGPRX2 antagonist, including pain conditions and rheumatology indications, beyond the initial focus on chronic spontaneous urticaria [20] - The use of innovative technologies, such as the AllergyScope for quantifying skin wheals, highlights Septerna's commitment to advancing clinical trial methodologies [15] Conclusion - Septerna is positioned to make significant advancements in the biopharmaceutical industry with its innovative drug discovery platform and promising pipeline, particularly in the areas of GPCR-targeted therapies and calcium regulation in hyperparathyroidism. The upcoming clinical trials and strong financial backing suggest a positive outlook for the company's future developments.

Summary of Septerna's Conference Call on SEP-631 Phase I Results Company Overview - **Company**: Septerna (NasdaqGM:SEPN) - **Focus**: Development of GPCR (G protein-coupled receptor) drug discovery, specifically targeting mast cell-driven diseases with their lead compound SEP-631 [2][4] Industry Context - **Target Disease**: Mast cell-driven diseases, including chronic spontaneous urticaria (CSU), atopic dermatitis, interstitial cystitis, migraine, and asthma [10][27][30] - **Market Opportunity**: High unmet medical need for effective treatments in mast cell-related conditions, particularly for patients refractory to current therapies [28][30] Key Points from the Conference Call Phase I Trial Results for SEP-631 - **Trial Design**: Randomized, double-blind, placebo-controlled study with single ascending doses (10 to 400 mg) and multiple ascending doses (10 to 200 mg) [18][19] - **Safety Profile**: - No severe or serious adverse events reported; treatment emergent adverse events comparable to placebo [19][20] - Mild transaminase elevations observed, not dose-related, and comparable to placebo [19][54] - **Pharmacokinetics**: - Elimination half-life of approximately 24 hours, supporting once-daily dosing [20][25] - No food effect observed, allowing for flexible dosing [20][25] Pharmacodynamics and Mechanism of Action - **Target Engagement**: Robust dose-dependent inhibition of MRGPRX2 signaling demonstrated through skin challenge tests [22][23] - **Efficacy**: Complete inhibition of icatibant-induced skin wheel formation at doses as low as 10 mg once daily [24][25] - **Mechanism**: SEP-631 acts as a negative allosteric modulator (NAM) with sub-nanomolar binding affinity, effectively closing the agonist binding pocket of MRGPRX2 [11][12][16] Future Development Plans - **Phase II Initiatives**: - Initiation of a Phase IIb study in chronic spontaneous urticaria planned for the second half of 2026 [27][29] - Exploration of additional indications including chronic inducible urticaria, atopic dermatitis, interstitial cystitis, migraine, and asthma [27][30] - **Clinical Strategy**: Focus on developing cost-efficient clinical plans to demonstrate proof of concept across various mast cell-driven diseases [31] Financial Position - **Capitalization**: Well-capitalized with a cash runway extending into 2029, allowing for continued investment in innovation and advancement of the pipeline [6][33] Strategic Partnerships - **Collaboration**: Ongoing strategic partnership with Novo Nordisk focused on five metabolic targets, enhancing the company's research capabilities [7][32] Additional Insights - **Market Positioning**: SEP-631 is positioned as a potential best-in-class treatment for mast cell-driven diseases, leveraging its unique pharmacological profile and favorable safety data [25][26] - **Research and Development**: Continuous evaluation of new indications and mechanisms related to mast cell activation, with a focus on understanding patient heterogeneity in response to treatments [81][80] This summary encapsulates the critical aspects of Septerna's conference call regarding SEP-631, highlighting the company's strategic direction, clinical findings, and market opportunities in the context of mast cell-driven diseases.

Phase 1 Results* for SEP-631, a Novel Oral Small Molecule MRGPRX2 Negative Allosteric Modulator (NAM) for Mast Cell-Driven Diseases March 2, 2026 Nasdaq: SEPN *Data presented at the 2026 American Academy of Allergy Asthma & Immunology (AAAAI) Annual Meeting © 2026 SEPTERNA Forward-Looking Statements This presentation contains express or implied forward‐looking statements of Septerna, Inc. (the "Company," "we," or "our") within the meaning of the Private Securities Litigation Reform Act of 1995, as amended. ...

Core Insights - Septerna, Inc. announced positive results from its Phase 1 clinical trial of SEP-631, a selective oral negative allosteric modulator targeting MRGPRX2, demonstrating robust inhibition of icatibant-induced skin wheal formation and well-tolerated across all doses studied [1][2][3] Phase 1 Results - SEP-631 was evaluated in a randomized, double-blind, placebo-controlled Phase 1 trial, showing a favorable pharmacokinetic profile supportive of once-daily oral dosing [3][5] - Complete inhibition of skin wheal formation was observed at doses as low as 10 mg once daily, with dose-dependent inhibition noted at higher doses [3][5] - The adverse event profile was comparable to placebo, with no severe or serious adverse events reported [5] Phase 2 Development Strategy - The company plans to initiate a Phase 2b clinical trial of SEP-631 in chronic spontaneous urticaria (CSU) in the second half of 2026, following ongoing long-term toxicology studies [4][6] - The Phase 2b study will be a randomized, double-blind, placebo-controlled trial evaluating once-daily oral SEP-631 in adult patients with moderate-to-severe CSU [6] Future Indications - Beyond CSU, Septerna is exploring additional mast cell-driven diseases with high unmet medical need, including atopic dermatitis, interstitial cystitis, migraine, and asthma [7][9] Company Overview - Septerna, Inc. is a clinical-stage biotechnology company focused on GPCR-targeted medicines, utilizing its proprietary Native Complex Platform for drug discovery [10]

Financial Data and Key Metrics Changes - The company has identified a new development candidate for its parathyroid hormone receptor program, moving forward after unexpected findings with a previous compound [3][5] - The new compound, SEP-479, shows significantly improved pharmaceutical properties compared to the discontinued SEP-786, with a lower effective dose in preclinical models [9][10] Business Line Data and Key Metrics Changes - The parathyroid hormone receptor program has transitioned to SEP-479, which has demonstrated the ability to normalize serum calcium levels in preclinical models [9][10] - The MRGPRX2 program has initiated a phase one trial with a randomized, placebo-controlled design, focusing on skin-based indications [14][15] Market Data and Key Metrics Changes - The company has formed a collaboration with Novo Nordisk, which includes a $195 million upfront payment and covers all R&D costs going forward, allowing the company to expand its programs without increasing its burn rate [46][47] Company Strategy and Development Direction - The company is focused on GPCR drug discovery, utilizing its Native Complex Platform to optimize compounds quickly and effectively [2][4] - The strategic partnership with Novo Nordisk aims to leverage their expertise in the metabolic space while pursuing multiple programs in parallel [46][47] - The company is exploring additional opportunities in areas such as osteoporosis, neurology, cardiovascular diseases, and respiratory diseases [50][51] Management's Comments on Operating Environment and Future Outlook - Management expressed confidence in the connection between preclinical data and eventual patient data for PTH peptides, indicating a strong potential for the new compound [21][22] - The company aims to gather safety and pharmacokinetic data in phase one trials to inform future patient dosing strategies [23][24] Other Important Information - The company has completed additional studies on SEP-786 to understand its effects better, particularly regarding bilirubin metabolism [7][8] - The company is optimistic about the potential for once-daily dosing with SEP-479, which could significantly improve patient compliance [31][32] Q&A Session Summary Question: When did the company start to see issues with bilirubin in the SINOS study for SEP-786? - The company observed bilirubin issues within a couple of days in the SINOS study, similar to findings in patients [18] Question: What is the development plan for SEP-479? - The company plans to conduct a phase one study with hopes of seeing safety and pharmacokinetic properties that will inform patient dosing [20][22] Question: How does SEP-479 differ from SEP-786? - SEP-479 is a completely different structural series with no observed functional differences in assays, but it is expected to have a lower risk of off-target effects [29][30] Question: What is the expected timeline for the phase one trial? - The company anticipates starting the phase one trial in the first half of next year, with more precise timing to be communicated later [34] Question: What is the opportunity within mast cell diseases for the MRGPRX2 program? - The company sees potential in various mast cell-driven diseases, including chronic spontaneous urticaria and atopic dermatitis, and plans to pursue multiple lead indications [35][40]

Core Insights - Septerna, Inc. is advancing its next-generation oral small molecule PTH1R agonist program for hypoparathyroidism, with plans to select a development candidate in Q3 2025 and initiate a Phase 1 clinical trial in H1 2026 [2][3] - The company is also initiating a Phase 1 clinical trial for SEP-631, an oral small molecule for mast cell diseases, in Q3 2025 [7] - Septerna's cash position is strong, with $379.2 million in cash and equivalents as of June 30, 2025, and an expected cash runway extending into 2029 following a $195 million upfront payment from Novo Nordisk [12][15] PTH1R Agonist Program - The PTH1R agonist program aims to provide full-day calcium control for patients with hypoparathyroidism, with a development candidate selection expected in Q3 2025 [3] - A Phase 1 clinical trial is planned to commence in the first half of 2026 after successful preclinical development [3] SEP-631 MRGPRX2 NAM Program - SEP-631 is a selective oral small molecule MRGPRX2 negative allosteric modulator for mast cell diseases, with a Phase 1 trial to assess safety and tolerability in healthy volunteers starting in Q3 2025 [7] Collaboration with Novo Nordisk - A global collaboration and license agreement with Novo Nordisk became effective on July 1, 2025, focusing on the discovery and development of oral small molecule therapies for obesity, type 2 diabetes, and other cardiometabolic diseases [7] - Septerna received a $195 million upfront payment as part of this collaboration [7] Business Highlights - The company continues to progress its TSHR NAM program, moving multiple lead compounds closer to development candidate selection for treating Graves' disease and thyroid eye disease [7] - Septerna's discovery-stage programs are advancing across various therapeutic areas utilizing its Native Complex Platform™ [7] Financial Results - For Q2 2025, Septerna reported R&D expenses of $22.2 million, up from $15.0 million in Q2 2024, and G&A expenses of $6.9 million, compared to $3.4 million in the same period [12] - The net loss for Q2 2025 was $24.8 million, compared to a net loss of $16.4 million in Q2 2024 [12][14]